The human body is armed
with an efficient and elegant immune system that fights pathogens and tumor
cells using T cells and antibodies made by B cells. Throughout the past century,
incredible advances have transformed the way we think about harnessing the immune
system’s potential to fight the most dreaded diseases.

Despite multiple immune
mechanisms that can be employed to fight diseases, the majority of vaccines
approved to date are thought to work principally through antibody responses
created by B cells only. Experts agree that the future of successful vaccine development
in infectious disease and in the fight against cancer is to go beyond the B
cell – and engage the T cell arm of the immune system to more comprehensively
employ the natural armament.

Attempts to date to create
immunotherapies based on directing T cell responses have largely focused on
engaging T cells to respond to known targets of B cell response – and have
often failed. These failures suggest that the key to harnessing the entire adaptive
immune system to fight disease is to identify the right T cell targets that
will induce a protective response.

This leaves vaccines and
immunotherapies at a critical crossroads – with a new technology poised to help
us see what was previously hidden and fully deliver on their promise.

THE T CELL CONUNDRUM

Unlike antibody targets,
which are typically surface-expressed or secreted proteins, T cell targets can
be derived from ANY protein in a pathogen or cancer, increasing the potential
target pool by up to a thousand-fold. Human genetic diversity further increases
the complexity. Here’s why. One of the first lines of defense in our body is
white blood cells called antigen-presenting cells (APCs). The job of an APC is
to sample its environment. For example, when a virus enters the body, a
patrolling APC will “eat” it and break down all of the viral proteins into
small pieces. The APC will then present some of the small pieces of the viral
proteins on its surface to nearby T cells that are trained to differentiate
“good” from “bad” pieces. Importantly, each person’s APCs have unique ways to
chop and present protein pieces to their own T cells. If the T cells recognize
the piece as “bad” then it will multiply, search for, and kill all cells harboring
the virus.

This means that in every person,
any piece of that virus has the potential to be recognized as foreign and
constitute an antigen, but not all are. As a result, the sheer volume of potential
antigens – a.k.a. T cell targets – in a complex pathogen or cancer and the
differences in how they may be presented by each person’s APCs makes reliable
predictions of which antigens to include in a vaccine virtually impossible. In addition,
just because a T cell can “see” the target, it does not necessarily mean that a
response to that antigen is protective. In fact, associations of T cell
responses with clinical outcomes are required to prioritize T cell antigens
effectively. The development of a tool that is able to cut through the
complexity of human diversity and the magnitude of potential targets, in order
to identify the right T cell antigens which drive a protective immune response,
could unlock a wealth of treatments to better fight diseases for which no good solutions
exist.

BETTER PROFILING, BETTER TARGETING

Genocea Biosciences is
working to remove these barriers by finding clinically relevant antigens (those
that elicit protective T cell responses) in diverse human subjects to guide the
development of new immunotherapies. At the core of the company’s mission to commercialize
key breakthroughs in vaccine and immunotherapy discovery and development is
Genocea’s proprietary technology, ATLASTM, which solves many of the
challenges associated with finding the right T cell targets. Using ATLAS,
Genocea is cultivating a pipeline of immuno-oncology and infectious
disease-related clinical and preclinical candidates.

ATLAS, a first of its
kind, proprietary rapid antigen-screening system identifies, via a cellular
assay, what the T cells of people who naturally protect themselves against disease
do differently than the T cells of those who don’t. In order to detect the most
important T cell responses, ATLAS is unbiased: rather than predicting which
antigens are meaningful, it instead takes a panoramic snapshot of actual human
T cell responses to any possible T cell target in a pathogen or cancer. By
associating these individual T cell response signatures with differential
clinical outcomes across large cohorts of patients, ATLAS can select the most clinically
relevant T cell targets for vaccine and immunotherapy development.

As a result, ATLAS winnows
what can be as many as several thousand candidate antigens down to a small set of
antigens that correlate with natural immunity. A subset is selected for in
vivo testing with the goal of identifying antigens for formulation and development
into vaccine candidates that will stimulate protective or therapeutic immunity
across diverse populations.

Because antigens are
identified by ATLAS using actual human immune responses to all potential
targets, by the time these candidates reach clinical trials, there may be a
greater likelihood of success in clinical development.

INNOVATION IN INFECTIOUS DISEASE

Genocea’s lead clinical
candidate is GEN-003, a first-in-class immunotherapy to treat genital herpes by
inducing both T cell and B cell (antibody) immune responses. GEN-003 has
demonstrated first-in-class results to date by showing statistically
significant reductions in clinical signs of genital herpes and viral shedding.
The antigens included in the GEN-003 vaccine were discovered using ATLAS.1

Genital herpes is a
serious and incurable sexually transmitted disease that affects more than 500
million people worldwide,2 including one out of six people between
the ages of 14 to 49 in the United States.3 The disease can cause
painful symptoms that include “outbreaks” in the form of blisters, usually on
or around the genitals and anus. People with genital herpes can still be highly
infectious even if they are not experiencing noticeable symptoms, and more than
80% of infected individuals ages 14 to 49 in the United States go undiagnosed.4
While available antiviral treatments can help prevent and shorten genital
herpes outbreaks,5 there is a significant unmet need for therapeutic
approaches that better control symptoms and viral shedding (the active viral
state when transmission risk is greatest).

In October 2015, Genocea reported
positive results from its Phase 2 trial of GEN-003 6 months post dosing. Vaccination
with GEN-003 resulted in a statistically significant 58% reduction from baseline
in the viral shedding rate, the primary endpoint of the study. The proportion
of patients receiving GEN-003 who were lesion-free at 6 months after dosing
ranged from approximately 30% to 50%, similar to results reported in clinical
trials with chronic administration of oral antiviral therapies. The study also
found that GEN-003 was safe and well tolerated by patients, with no serious
adverse events related to the vaccine.

GEN-003 most recently demonstrated
sustained and statistically significant reductions compared to baseline in the
rate of viral shedding 12 months after dosing, with sustained efficacy at
multiple dose levels across secondary endpoints measuring the impact on
clinical disease. The company has advanced the two most promising doses, of 60
μg per protein combined with either 50 or 75 μg of Matrix-M2TM
adjuvant, from this Phase 2 dose optimization study into an ongoing Phase 3 efficacy
trial. Later this year, the company will report virologic and clinical efficacy
data using potential Phase 3 endpoints from the Phase 2B trial, confirming the
activity of GEN-003 manufactured at larger scale. Genocea will also commence a
Phase 2B antiviral combination study in the second half of 2016.

GEN-003 has the potential
to become a cornerstone treatment for genital herpes patients. A single course of
GEN-003 may offer genital herpes patients efficacy similar to a full year of daily
administration of oral antivirals – but with vastly improved convenience. Furthermore,
in contrast to the dominant treatment paradigm of episodic antiviral treatment,
GEN-003’s ability to reduce viral shedding could decrease the frequency of
genital lesion outbreaks and may potentially lower the risk of disease transmission
for these patients.

ATLAS & IMMUNO-ONCOLOGY: CHARTING A CLEARER PATH FORWARD

ATLAS’ capabilities are
currently also being leveraged to help take the guesswork out of cancer vaccine
T cell target discovery and better identify patients most likely to respond to immuno-oncology
therapies through partnerships with the Dana-Farber Cancer Institute and
Memorial Sloan Kettering Cancer Center.

The Dana-Farber Cancer Institute
collaboration sees Genocea using ATLAS to study tumor-associated antigens in
melanoma patients treated with checkpoint inhibitors. By profiling their T cell
responses to different cancer antigens, Genocea may be able to understand their
clinical relevance. A retrospective analysis of the T cell responses from
checkpoint inhibitor-treated patients against known tumor-associated antigens
revealed that ATLAS had successfully identified the cancer antigens to which T
cells naturally had become activated. This research also demonstrated a pattern
indicating that different characteristics of T cell responses emerge in
patients who responded to checkpoint inhibitor therapy versus those who did
not.

In the Memorial Sloan
Kettering Cancer Center collaboration, Genocea is using ATLAS to screen the T
cell responses of melanoma and non-small cell lung cancer patients treated with
checkpoint inhibitors against their own, patient-specific tumor neoantigens.
This research is aimed at identifying signatures of protective T cell responses
with the goal of potentially discovering new cancer vaccine T cell antigens.

The research conducted by
Genocea alongside these leading academic centers demonstrates ATLAS’
flexibility to help optimize the development of both universal and personalized
cancer vaccines. When applied across large diverse populations against common tumor-associated
antigens, ATLAS may discover better targets to include in cancer vaccines,
which could potentially help them work more broadly across different patient
populations. When applied to an individual’s response to their own cancer
neoantigens, ATLAS may enable better personalized cancer vaccines, either as
standalone therapies or in combination with other immunotherapies, such as
checkpoint inhibitors.

With additional data from
its ongoing immuno-oncology collaborations expected in 2016, Genocea
anticipates initiating trials for a personalized cancer vaccine candidate in 2017.

CONCLUSION

Based on the information
and insights gleaned from ATLAS, Genocea has been able to successfully define targets
of human T cell responses that become central to novel vaccines and immunotherapies,
and demonstrate success in a clinical setting. Effective therapies which direct
T cells against cancer and infectious diseases could revolutionize healthcare
and improve outcomes for patients affected by these illnesses. The right T cell
targets, discovered with ATLAS, are the key to unlocking the full promise of T
cell therapies, finding solutions for the most challenging and hardest to treat
diseases.

Dr.
Jessica Baker Flechtner joined Genocea in 2007, soon after the
company was founded, and currently serves as the Chief Scientific Officer. Dr.
Flechtner is a pioneer in the development of novel vaccines directed toward T
cell immunity and has more than 18 years of experience in immunology,
infectious disease, cancer, and vaccine development. She leads Genocea’s efforts
to develop T cell-directed vaccines and immunotherapies against infectious diseases
and other indications. Prior to joining Genocea, Dr. Flechtner developed
vaccines and immunotherapies for cancer, infectious disease, autoimmunity, and
allergy in several companies, including Mojave Therapeutics and Antigenics Inc.
(now Agenus). She is an inventor on seven pending and three issued patents and
has multiple peer-reviewed scientific publications. Dr. Flechtner performed her
post-doctoral work at the Dana-Farber Cancer Institute and Harvard Medical School.
She earned her PhD in Cellular Immunology and her BS in Animal Science from
Cornell University, and is a member of the American Association of
Immunologists and American Society for Microbiology.